Clearance Assessment and Modeling

Progressive methods and tools to approach PK in minors:

Clearance Assessment and ModelingJoachim Grevel, Merck Serono, Human Pharmacology, Geneva, Switzerland

2/2/2009 Joachim Grevel 2

Lecture overview

• The « safe » road to pediatric dose selection (15 min)

Separating growth from maturation

Allometric principle

Methodology

• The « progressive » road to pediatric dose selection (10 min or less)

Low test dose, a nice idea

PET studies

HPLC-AMS


When attempting to predict PK in children the covarying effects of growth (size, weight) and maturation (postmenstrual age) need to be separated.

Population PK modeling can accomplish this…


Estimated allometric coefficient: 0.742 (indistringuishable from 0.75)

Separating effect of weight on CL ….

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For neonates the under-estimation of CL may, by accident, capture the immature pathways.

…still separating effect of weight on CL …


After 2 years of age metabolic pathways seem matured.

…from the effect of age on CL


Maturation of clearance: a function of age

Key time points:

- 40 weeks PMA (normal birth): placenta as external clearance organ with CYP and conjugation activity is being separated.

- 6 months PNA: glomerular filtration rate reaches adult value of 6(L/h/70kg); GFR is thereafter only SIZE dependent.

There is no direct demonstration that clearance changes as a consequence of being born…

pathways involved in clearance already delelop in utero… (Nick Holford, 2008)


Maturation of GFR with PMA: median and 90% C.I. The model contains an allometric relationship for size and a sigmoid Emax relationship for age (maturation). Even though all nephrons (106) are in place at PMA=36 weeks, kidneys are immature at birth.Anderson BJ, Holford NHG Annu Rev Pharmacol Toxicol 2008; 48:303-32.

Maturation of GFR


Volume of distribution

Separating effect of size (weight) from effect of maturation (age)…

Effect of size (weight):

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Effect of maturation is more complicated and needs to be modeleddrug-specifically…


Changes in Volume of distribution (body composition):

-Total body water: 85% of weight preterm; 75% of weight full-term; 60% at 5 months and thereafter

-Extracellular fluid: 45% of body weight at birth; 26% at one year; 18% in adulthood

-Fat: 3% in premature neonate; 12% in full-term neonate; decrease when infant starts walking; large cultural and genetic differences thereafter

-Protein: 20% full term neonate; 50% lean adult

-Plasma binding partners: albumin, globulin, lipoprotein, glycoprotein change during first year of life

Developmental changes of V


In terms of pharmacokinetics, children are just small adults – babies are immature children. (NHG Holford)With allometric scaling (“top-down”) from PK models in adults one can arrive at useful starting points for designing PK studies in children (>= 2 years).

Pharmacodynamic differences between adults and children need to be investigated. (Back-up slides)

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For younger children one can apply physiology-based PK modeling ("bottom-up").

Remark: Scaling CL with body surface area (Du Bois & Du Bois, 1916) is equivalent to scaling with an exponent of 2/3. For humans between 20 and 120 kg the approach is almost identical to the ¾ power rule.

Top-down, bottom-up


i.v. midazolam oral caffeine

In silico approach (Simcyp® University of Sheffield) is performing well in the very young age group.

Johnson TN, Rostami-Hodjegan A, Tucker GT; Clin Pharmacokinet 2006: 45: 931-956

Bottom-up: PBPK-approach


The Simcyp® software uses:

• in vitro drug metabolism data,

• a large data base of physiologic data of children

• physicochemical properties of the drug

The Simcyp® software predicts:

• median profiles for children of all ages,

• population variability and central tendency,

• covariate features which lead to extreme exposure.

Bottom-up: PBPK-approach



Watching PBPK modeling at work…

Thanks to Jörg Lippert of Bayer Technologies with PKSIM®!


Watching PBPK modeling at work…Thanks to Jörg Lippert of Bayer Technologies!


Watching PBPK modeling at work…

Thanks to Jörg Lippert of Bayer Technologies!


Back-up slides:

PD differences between adults and children 20

PET (Positron Emission Tomography)21

Application of PET in PK, PD22

HPLC-AMS after microdosing (1st slide)23

HPLC-AMS after microdosing (2nd slide)24

Small versus large molecules: predicting pediatric PK25

Nice idea: « small test dose »19

TopicNr.


Nice idea: … a small test dose.. perhaps even so small that it can only be detected when the compound is labeled (14C, or positron-emitting for PET)

…The small test dose will be perfectly safe and one can determine CL based on a few optimal PK samples…

…with that CL in place (perhaps even a V) one can calculate the optimal dose for the pediatric trial. A dose that will be safe and efficacious…

1st Caveat: dose-dependency of absorption, distribution, and elimination over a dose range of 100 to 1000; PD in children is not necessarily the same as in adults.

2nd Caveat: The children participating in the test dose trial have zero benefit but not necessarily zero risk (i.v. dose, radiolabel, confinement)

…but it is unlikely to work.

Title back-up slide:

Original sub-title: “…low dose administration for clearance assessment…”


Optimizing the dose according to PK makes only sense when PD is the same between children and adults. Here some exceptions:

De Wildt et al. (2001)

less sedation at same conc. for all ages in the study

31preterm to 29 weeks

Midazolam

Takahashi et al. (2000)

longer delay of clotting at same conc. 1-11y

1341-76yWarfarin

Marshall & Kearns (1999)

More response (immunosuppr.) at same conc. 1-4y

563 mo-39yCyclosporine

ReferenceObservationnAge rangeDrug

PD difference between adults and children


1st PET back-up slide

PET tracer is usually administered as i.v. bolus with typical amount of 5 μg

with 11C labelling studies are limited to 2 hours (with 18F to 8 hours)

at the low tracer concentrations (1000 less than therapeutic) high-affinity low-capacity binding sites can distort PK

at least dose-linearity (nonlinearity) would have to be defined in adults over the range from tracer to therapeutic concentrations, before PET can be useful for PK predictions in children

metabolic stability of tracer needs to be established (at least in adults), otherwise simutaneous plasma HPLC needs to determine the fraction of parent drug (almost prohibitive in children

Conclusion: PET studies to determine PK after microdosing are almost inconceivable in children.


2nd PET back-up slide

PK with PET:-required radiolabelled (11C T1/2=20 min, 18F T1/2=110 min) investigational drug

-doses within EMEA definition (<1/100 of pharmacologically active dose and<=100 μg) and given i.v. only

-no separation of parent and metabolite in tissue, thus simultaneous plasma HPLC is necessary

PD with PET:-involves therapeutic doses of unlabelled investigational drug and

-either radiolabelled validated biomarker or

-radiolabelled validated receptor ligand


Problem with microdosing of 14C labeled drug and HPLC-AMS* detection:

Formulation: always liquid for microdose! Distribution

2 of 5 test drugs had problems

* AMS…accelerator mass spectrometry

HPLC-AMS

oral microdose: stability in gastric and intestinal fluid needs to be established.


It can also work nicely:

HPLC-AMS back-up slide


Small versus large molecules: predicting pediatric PK

-binding = elimination*

-neither hepatic nor renal++

-hepatic, maturation

-renal, maturation

Elimination

Large molecule « biologic »Small molecule « drug-like »PK phase

+ plasma composition, maturation of immune system

* target-mediated++ small biologics may be filtered (pore diameter 50-100 nm)

-binding+ in plasma

-binding+ in tissue

-binding+ in plasma

-volume

Distribution

-s.c. dose (depot)

-skin composition

-oral dose (solid, liquid)

-GI transit, maturation

-first-pass effect, maturation

Absorption


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Clearance Assessment and Modeling